Bicyclic heteroarenes and methods of their use

A compound, or pharmaceutically acceptable salt thereof, having the structure:

• or a pharmaceutically acceptable salt thereof,
• wherein X2 is N or CH;
• RA is optionally substituted C2-C9 heteroaryl;
• or optionally substituted C6-C10 aryl;
• R1 is optionally substituted C2-C9 heteroaryl or —O—R7;
• R2 is hydrogen or optionally substituted C1-C6 alkyl;
• and
• R7 is optionally substituted C2-C9 heteroaryl C1-6 alkyl.

A compound of the following structure:

• #
• Compound
• 1
• 2
• 3
• 4
• 5
• 6
• 7
• 8
• 9
• 10
• 11
• 12
• 13
• 14
• 15
• 16
• 17
• 18
• 19
• 20
• 21
• 22
• 23
• 24
• 25
• 26
• 27
• 28
• 29
• 30
• 31
• 32
• 33
• 34
• 35
• 36
• 37
• 38
• 39
• 40
• 41
• 42
• 43
• 44
• 45
• 46
• 47
• 48
• 49
• 50
• 53
• 54
• 55
• 56
• 57
• 58
• 59
• 60
• 61
• 62
• 63
• 64
• 65
• 66
• 76
• 77
• 78
• 79
• 80
• 81
• 86
• 87
• 88
• 89
• 90
• 91
• 92
• 98
• 99
• 100
• 101
• 102
• 103
• 104
• 105
• 106
• 107
• 108
• 109
• 110
• 111
• 112
• 113
• 114
• 115
• 116
• 117
• 118
• 119
• 120
• 121
• 126
• 127
• 128
• 129
• 130
• 132
• 135
• 151
• or a pharmaceutically acceptable salt thereof.

A compound of the following structure:

• #
• Compound
• 51
• 52
• 67
• 68
• 69
• 70
• 71
• 72
• 73
• 74
• 75
• 82
• 83
• 84
• 85
• 93
• 94
• 95
• 96
• 97
• 122
• 123
• 124
• 125
• 131
• 133
• 134
• 136
• 137
• 138
• 139
• 140
• 141
• 142
• 143
• 144
• 145
• 146
• 147
• 148
• 149
• 150

A method of treating a TDP-43-associated disorder in a subject, the method comprising administering to the subject in need thereof an effective amount of the compound of formula (14):

• or a pharmaceutically acceptable salt thereof,
• wherein
• is a single bond, X1 is (C(RA)2)m or —OC(RA)2—RX, and X2 is C(RA)2 or CO;
• or is a double bond, and each of X1 and X2 is independently CRA or N, wherein RX is a bond to X2;
• R1 is —(L)n—RB, hydrogen, halogen, cyano, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C1-6 alkoxy, optionally substituted C6-10 aryl, optionally substituted C1-9 heterocyclyl, or optionally substituted C1-9 heteroaryl;
• R2 is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heterocyclyl, optionally substituted C1-9 heteroaryl, or optionally substituted C6-C10 aryl C1-C6 alkyl;
• R3 is a group of the following structure:
• each RA is independently H, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, or two geminal RA groups, together with the atom to which they are attached, combine to form oxo;
• RB is optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C3-8 cycloalkyl, —N═CH—RD, or optionally substituted C1-9 heterocyclyl, optionally substituted C2-C9 heteroaryl C1-6 alkyl, optionally substituted C2-C9 heterocyclyl C1-6 alkyl;
• RC is H or optionally substituted C1-C6 alkyl;
• RD is optionally substituted C6-C10 aryl;
• each L is independently optionally substituted alkylene, optionally substituted C1-C6 heteroalkylene, optionally substituted C3-C8 cycloalkylene, optionally substituted C2-C6 alkynylene, O, or NRC;
• and
• n is 1, 2, or 3;
• and
• m is 0, 1, or 2.